Ions and membrane phospholipids can undergo dynamic transbilayer movement. While membrane ion transport mediated by ion channels and pumps is well appreciated in health and disease, the molecular mechanism, cellular function, physiological and pathological importance of membrane phospholipid transport are still poorly understood. Recently, I and others discovered that the newly discovered TMEM16 membrane protein family includes both ion channels and lipid scramblases. These findings open up unique opportunities to tackle the poorly understood lipid transport phenomenon. I propose herein a novel phospholipid-mediated cell signaling paradigm that is distinct from the canonical lipid signaling mechanism. In this paradigm, phospholipids, instead of being enzymatically metabolized, undergo dynamic transbilayer redistribution. This rapid transbilayer lipid transport mediated by TMEM16F lipid scramblase can spatiotemporally change the local/global lipid composition, and subsequently alter the membrane association of various signaling proteins and their downstream signaling cascades. I will test this new signaling paradigm by genetically and pharmacologically manipulating the TMEM16F- mediated phosphatidylserine (PS) exposure. Particularly, I will examine the effects of TMEM16F- mediated phospholipid transport on the PS binding proteins and their downstream signaling pathways in vitro. I will examine the physiological roles of TMEM16F in the excitable neurons and nonexcitable glial cells, two major cell types in the brain, to investigate the in vivo functions of the lipid scramblase. I will also develop pharmacological reagents to manipulate TMEM16F function. My overall goal is to understand the molecular, cellular and physiological mechanisms of transbilayer lipid phenomenon and its impacts on human health and disease.

Public Health Relevance

The flip-flop of phospholipids across cell membranes happens in every human cell. According to our limited knowledge, this transmembrane lipid movement is critical for blood clotting and also is an important step during cell death. Nevertheless, the misconceptions about the phospholipid transport have prevented us from further understanding of its importance in human health and disease. In this project, I propose a new cell signaling paradigm to explain the cellular functions of the understudied transmembrane phospholipid transport phenomenon. Using multidisciplinary approaches to manipulate the newly discovered TMEM16F lipid transporter, I will test this new paradigm, characterize its physiological and pathological functions in the brain and discover new reagents to target lipid transport. This important membrane phenomenon exists in many different cell types. Thus, my findings will generate big impact in the biomedical filed, and will help to understand the biological basis of many physiological processes and disease conditions. The reagents discovered in this project will have great therapeutic potentials to treat disease such as stroke, heart attack, arthritis, cancer and ataxia.